While T cell mediated autoimmune insulin dependent diabetes mellitus (IDDM) in both humans and NOD mice is controlled by multiple susceptibility (Idd) genes, particular MHC haplotypes provide the primary component of pathogenesis. Within the MHC, unusual class II alleles clearly contribute to IDDM by controlling the development of CD4+ T cells autoreactive against insulin producing pancreatic beta cells. However, we have found that while they represent common alleles shared by many strains without autoimmune proclivity, the Kd and/or Db class I molecules encoded within the H2g7 MHC haplotype of NOD mice exert a diabetogenic role which initiates the earliest phases of beta cell destruction by CD8+ T cells. Our first aim is to test the hypothesis that these common MHC class I gene products acquire autoimmune functions through interactions with other immunological factors characterizing NOD, but not IDDM resistant strains. This will be done by determining through genetic outcross studies what immunological functions must present to maintain the greatly accelerated rate of IDDM development observed in a new stock of NOD mice transgenically expressing a T cell receptor (TCR) specific for a H2g7 MHC class I restricted beta cell autoantigen. Preliminary data indicate that allelic variants of beta2-microglobulin (beta2m) may represent a non-MHC Idd gene through an ability to differentially alter MHC class I function. Our second aim is to determine if one component of IDDM susceptibility in NOD and resistance in H2g7 identical NOR mice is provided by allelic variants of beta2m that controls the ability of MHC class I molecules shared by these two strains to elicit diabetogenic T cell responses. This will be tested by comparing the ability of transgenes encoding various beta2m isoforms to modulate IDDM development. Since MHC class I dependent T cells initiate autoimmune beta cell destruction, inducing tolerance to antigens recognized by these effectors could be an effective means of inhibiting IDDM. However, to date, no MHC class I restricted beta cell autoantigens targeted in IDDM have been identified. Thus, our third aim is to identify beta cell autoantigens that are targets of MHC class I restricted T cells contributing to the initiation of IDDM in NOD mice. Peptides eluted from MHC class I molecules expressed on NOD pancreatic beta cell tumors will be tested for ability to stimulate diabetogenic T cell clones. We will then determine if NOD mice can be rendered tolerant to these MHC class I restricted beta cell autoantigens by a method we have successfully used for other antigens.